(PTFS11-03-24) Hyperthermia Treatment Attenuates Diet-Induced Obesity and Insulin Resistance in Old Female and Ovariectomized Mice via TRPV1-Mediated Futile Calcium Cycling

Objectives: Recent research highlights a substantial decline in energy expenditure in older adults, urging the development of a targeted health strategy to address this decline. Hyperthermia or heat treatment (HT) is an emerging therapeutic approach with demonstrated metabolic benefits. However, whether HT effectively promotes metabolic health by overcoming aging- or menopause-associated metabolic slowdown remains unexamined. This study aims to investigate the impact of HT on attenuating obesity and metabolic dysfunction in old female mice and elucidate the underlying molecular mechanisms.

Methods: Ten-month-old female C57BL/6 mice and ovariectomized (OVX) mice were utilized to model aging and post-menopausal conditions, respectively. Mice were fed a Western diet (45% calories from fat) to induce obesity, and with or without daily HT for 30 minutes by placing them in a 40℃ ventilated heat chamber for 12 weeks. Effects of HT on body composition, weight gain, insulin sensitivity, blood lipids, glucose profiles, and metabolic adaptation were assessed, including core body temperature and lipid metabolism transcription levels in adipose tissue and liver. Human white and brown adipocytes were used to confirm the metabolic impact of heat exposure.

Results: Daily HT at 40℃ showed no tissue damage and significantly reduced lactate dehydrogenase (LDH) levels in older females, indicating a decline in aging-mediated tissue damage. HT effectively countered weight gain induced by high fat diet in both aged female and ovariectomized mice. Furthermore, HT demonstrated significant improvements in: 1) insulin sensitivity and insulin signaling in inguinal white adipose tissue (iWAT), 2) reduced lipid accumulation in the liver and brown fat, and 3) increased fatty acid beta-oxidation in the liver and iWAT. The elevated expression of transient receptor potential vanilloid 1 (TRPV1) and genes associated with Ca2+/ATP-pump on the plasma membrane and ER suggests that HT triggers ATP-consuming futile calcium cycling. These findings were confirmed in human brown and white adipocytes.

Conclusions: Whole-body heat therapy effectively reduces aging and menopause-associated obesity and insulin resistance by activating TRPV1, inducing futile calcium cycling, and promoting thermogenic energy expenditure.

Funding Sources: University of Massachusetts Amherst